The ras family of oncogenes and proto-oncogenes encode certain proteins which are implicated in the control of eukaryotic cell proliferation. These genes, through the normal transcription and translational processes, provide proteins called ras proteins which can interact with effector molecules to control cell division.
Ras proteins are initially produced in the cell in an inactive state and must undergo various post-translational modifications in order to become activated. As part of the activation process, the ras proteins undergo farnesylation at a cysteine residue located near the C-terminus. This farnesylation facilitates the association of the ras protein with the inner surface of the plasma membrane. Membrane association is critical for the oncogenic transformation caused by activated ras proteins. See Schafer et al., Science 245, 379 (1989).
The farnesylation of ras proteins is catalyzed by the enzyme ras farnesyl:protein transferase, also known as FPTase. Through this enzymatic reaction, the farnesyl moiety of the cholesterol biosynthetic intermediate, farnesyl diphosphate, is linked through a thioether bond to a cysteine residue located near the C-terminus of the ras protein.
Activated ras proteins are found in a variety of human cancers including colon and pancreatic carcinomas. Interference of membrane localization by ras proteins by inhibition of the FPTase-mediated farnesylation of inactive ras proteins, will inhibit cell proliferation caused by activated ras proteins and will thus provide an anticancer effect.
The present invention provides compounds which are inhibitors of ras FPTase and as such are useful as anticancer agents.